Aberrant stress-induced phosphorylation of perikaryal neurofilaments.

The aberrant phosphorylation of the neurofilament high molecular weight subunit (NFH) in the neuronal perikaryon is a common feature of several neurological diseases. We demonstrated a strong correlation between hyperphosphorylation of the NFH carboxyl-terminal domain and activation of stress-activated protein kinase (SAPK) -gamma in PC12 cells. Agents that activated SAPKgamma in PC12 cells also caused the hyperphosphorylation of perikaryal NFH in cultured dorsal root ganglion neurons. The NFH carboxyl-terminal domain was phosphorylated by SAPKgamma in vitro, and the use of peptide substrates indicated that this event occurred preferentially at KSPXE motifs. We propose that SAPKgamma, perhaps in concert with other SAPKs, is involved in the abnormal phosphorylation of perikaryal NFH. This finding could lead to new insights into the etiology of several neurological diseases.